Bioreactor studies have increasingly focused on immobilized cell systems [Chibata et al, Ann. Rev. Biophys. Bioeng., 1981, 10: 197; Margaritis et al, CRC Crit. Rev. Biotechnical, 1: 339 (1981); Inloes, "Immobilization of Bacterial and Yeast Cells in Hollow-Fiber Membrane Bioreactors", 1982, Ph.D. Thesis, Stanford University; Nagashima et al, Biotechnical, Bioeng., 26: 992 (1984)]. Possible improvements in productivity due to high cell densities has been a motivating factor. However, cell immobilization may not give increases of productivity in some systems due to feedback inhibition. In these cases integration of production and recovery in the same unit may be advantageous. The integration of bioconversion and separation to improve the productivity of a bioreactor has been considered, [Wang, Ann. NY Acad. Sci., p. 313 (1983); Kominek, Antimicrob. Agents Chemother, 7: 856 and 861 (1971); Finn, J. Ferm Technol., 44: 305 (1966], although few of these studies have focused on immobilized microbes. Since downstream product recovery is often a significant cost (both in money and energy), the challenge comes from not only the improvement of productivity in the bioreactor but also to reduce downstream processing costs.
The effects of feedback inhibition are well known, [Brown et al, Euro. J. Appl. Microbiol. Biotechnol., 11: 151 (1981); Ghose et al, Biotechnol. Bioeng., 21: 1401 (1979); Luong, Biotechnol. Bioeng., 27: 280 (1985); Aiba et al, Biotechnol. Bioeng., 10: 845 (1985); Holzberg et al, Biotechnol. Bioeng., 9: 413 (1967)].
Heretofore the potential of immobilized or entrapped cell systems to greatly improve volumetric productivity in bioreactors has been limited, due in part, to the effects of diffusional limitations on nutrients or metabolic products. For example, if the desired product is inhibitory to its own formation and it can not be effectively transported away from the point of synthesis, the reaction will slow down or may even stop.
Various researchers have attempted to circumvent feedback inhibition and to integrate production and recovery: Wang, H. Y., Ann. N.Y. Acad. Sci., 313: (1983); Kominek, L. A., Antimicrob. Agents Chemother., 7: 856 and 861 (1975); Finn, R. K., J. Ferm. Technol, 44: 305 (1966); Choudhurg, J. P. et al., Biotechnology Letters, 8 (10): 731-734 (1986); Vieth W. R. et al, Bioprocessing Technology, 8 (3): 8 (1986).
Cho, T. and M. L. Shuler, Biotech. Prog., 2: 53 (1986) described the operation of an immobilized cell multimembrane bioreactor, in which production and recovery were integrated. Finn, R. K., and Ercoli, E. (ALS Symposium Series, 314,44 (1986)), have used a simple two compartment reactor unit employing a hydrophilic membrane and cycling the presence in each compartment, to remove inhibitory acidic products formed by rumen bacteria.
Although many of these approaches are useful outside of the particle or unit immobilizing the cell mass, there is an unfilled need to minimize or reduce diffusional limitations in an entrapped or immobilized cell mass.
An improved membrane cell bioreactor and process that gives enhanced product yields in both feedback inhibited and nonfeedback inhibited systems is advantageous and would be adaptable to a wide range of biological cell reactions.